Background: Congenital scoliosis is frequently associated with anomalies in multiple organ systems. However, the prevalence and distribution of associated anomalies remain unclear, and there is a large amount of variation in data among different studies.Methods: Six hundred and thirty-six Chinese patients who had undergone scoliosis correction surgery at Peking Union Medical College Hospital from January 2012 to July 2019 were recruited, as a part of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study. The medical data for each subject were collected and analyzed.Results: The mean age (and standard deviation) at the time of presentation for scoliosis was 6.4 ± 6.3 years, and the mean Cobb angle of the major curve was 60.8°± 26.5°. Intraspinal abnormalities were found in 186 (30.3%) of 614 patients, with diastematomyelia being the most common anomaly (59.1%; 110 of 186). The prevalence of intraspinal abnormalities was remarkably higher in patients with failure of segmentation and mixed deformities than in patients with failure of formation (p < 0.001). Patients with intraspinal anomalies showed more severe deformities, including larger Cobb angles of the major curve (p < 0.001). We also demonstrated that cardiac anomalies were associated with remarkably worse pulmonary function, i.e., lower forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF). Additionally, we identified associations among different concomitant malformations. We found that patients with musculoskeletal anomalies of types other than intraspinal and maxillofacial were 9.2 times more likely to have additional maxillofacial anomalies.Conclusions: In our cohort, comorbidities associated with congenital scoliosis occurred at a rate of 55%. To our knowledge, our study is the first to show that patients with congenital scoliosis and cardiac anomalies have reduced pulmonary function, as demonstrated by lower FEV1, FVC, and PEF. Moreover, the potential associations among concomitant anomalies revealed the importance of a comprehensive preoperative evaluation scheme.

Recurrent proximal 16p11.2 deletion (16p11.2del) is a risk factor for diverse neurodevelopmental disorders (NDDs) with incomplete penetrance and variable expressivity. Although investigation with human induced pluripotent stem cell (hiPSC) models has confirmed disruption of neuronal development in 16p11.2del neuronal cells, which genes are responsible for abnormal cellular phenotypes and what determines the penetrance of neurodevelopmental abnormalities are unknown. We performed haplotype phasing of the 16p11.2 region in a 16p11.2del NDD cohort and generated hiPSCs for two 16p11.2del families with distinct residual haplotypes and variable NDD phenotypes. Using transcriptomic profiles and cellular phenotypes of the hiPSC-differentiated cortex neuronal cells, we revealed MAPK3 as a contributor to dysfunction in multiple pathways related to early neuronal development, with altered soma and electrophysiological properties in mature neuronal cells. Notably, MAPK3 expression in 16p11.2del neuronal cells varied based on a 132 kb 58 SNP residual haplotype, with the version composed entirely of minor alleles associated with reduced MAPK3 expression. Ten SNPs on the residual haplotype map to enhancers of MAPK3. We functionally validated six of these SNPs by luciferase assay, implicating them in the residual haplotype-specific differences in MAPK3 expression via cis-regulation. Finally, the analysis of three different cohorts of 16p11.2del subjects showed that this minor residual haplotype is associated with NDD phenotypes in 16p11.2del carriers.

TBX6 encodes transcription‐factor box 6, a transcription factor critical to paraxial mesoderm segmentation and somitogenesis during embryonic development. TBX6 haploinsufficiency is believed to drive the skeletal and kidney phenotypes associated with the 16p11.2 deletion syndrome. Heterozygous and biallelic variants in TBX6 are associated with vertebral and rib malformations (TBX6‐associated congenital scoliosis) and spondylocostal dysostosis, and heterozygous TBX6 variants are associated with increased risk of genitourinary tract malformations. Combined skeletal and kidney phenotypes in individuals harboring heterozygous or biallelic TBX6 variants are rare. Here, we present seven individuals with vertebral and rib malformations and structural kidney differences associated with heterozygous TBX6 gene deletion in trans with a hypomorphic TBX6 allele or biallelic TBX6 variants. Our case series highlights the association between TBX6 and both skeletal and kidney disease.